Pharmacokinetics of a slower clearing tissue plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction.
The rapid clearance of t-PA from plasma requires administration by intravenous (I.V.) infusion. A slower clearing, fibrin-specific rt-PA variant may allow single intravenous bolus administration, thereby simplifying dosing. This study was designed to characterize the pharmacokinetics of the slower clearing, fibrin-specific tissue-plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction (AMI) following a single I.V. bolus injection. Single I.V. bolus doses of 5 to 50 mg of TNK-tPA were studied in an open-label, multicenter, dose escalation study. A total of 113 AMI patients were enrolled. Blood sampling for pharmacokinetics was conducted in eighty-two patients (72 men, 10 women), with 5 to 27 patients per dose. TNK-tPA was administered as an I.V. bolus over 5-10 s. Following I.V. bolus administration, there was a biphasic elimination of TNK-tPA from plasma. The initial phase had a mean half-life that ranged from 11 +/- 5 to 20 +/- 6 min and was followed by a terminal phase with a mean half-life that ranged from 41 +/- 16 to 138 +/- 84 min. Mean TNK-tPA plasma clearance was 125 +/- 25 - 216 +/- 98 ml/min, and the initial volume of distribution was 4.3 +/- 2 - 8.4 +/- 6 1. A decrease in TNK-tPA plasma clearance with increasing TNK-tPA dose was noted. In addition, women and patients with lower body weight or older age had a slower plasma clearance. In conclusion, TNK-tPA has a slower plasma clearance in patients with AMI than that reported for rt-PA, allowing administration as a single I.V. bolus.
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Department of Pharmacokinetics and Metabolism, Genentech, Inc., S. San Francisco, CA, USA. nishit.modi@alza.com
Eppler
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Breed
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Cannon
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Braunwald
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Love
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D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000188:drug therapy; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000493:pharmacokinetics*
C104096:TNK-tissue plasminogen activator; D010959:Tissue Plasminogen Activator